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Group II phospholipase A2 as an autocrine growth factor mediating interleukin-1 action on mesangial cells
1First Department of Medicine, Osaka University School of Medicine, Japan.
Abstract:
The proliferation of mesangial cells plays a central role in the progression of glomerulonephritis. We studied the role of group II phospholipase A2 in interleukin-1-stimulated proliferation of mesangial cells. Cultured rat mesangial cells secreted 5.3 units group II phospholipase A2/24 h per 10(5) cells in response to stimulation of 200 U/ml of interleukin-1. Northern hybridization analysis showed that mRNA for group II phospholipase A2 was induced by exogenously added group II phospholipase A2 (15 U/ml) as well as interleukin-1. The pretreatment of quiescent mesangial cells with interleukin-1 augmented [3H]thymidine incorporation caused by platelet derived growth factor. Exogenous group II phospholipase A2 (5-36 U/ml) purified homogeneously from rat spleen also increased [3H]thymidine incorporation by platelet derived growth factor-stimulated mesangial cells in a dose dependent manner (36 U/ml phospholipase A2; 1.9-fold). The stimulatory effect of interleukin-1 on DNA synthesis of mesangial cells was specifically blunted by immunoglobulin raised against group II phospholipase A2. Group II phospholipase A2 (16 U/ml) amplified a platelet derived growth factor-stimulated increase in the mesangial cell number by 1.5-fold. Among the products of the phospholipase A2-catalyzed reaction, lysophospholipids including lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidic acid, but not fatty acids, mimicked the stimulatory effect of interleukin-1 and phospholipase A2. These results suggest that group II phospholipase A2 acts as a signaling molecule that mediates interleukin-1-induced growth of rat mesangial cells through yielding lysophospholipids.
Insights
Group II phospholipase A2 (PLA2) promotes interleukin-1-induced mesangial cell proliferation in glomerulonephritis. This signaling molecule yields lysophospholipids, contributing to kidney disease progression.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- Mesangial cell proliferation is critical in glomerulonephritis progression.
- Interleukin-1 (IL-1) is a key inflammatory mediator in kidney disease.
Purpose of the Study:
- To investigate the role of group II phospholipase A2 (PLA2) in IL-1-stimulated mesangial cell proliferation.
- To elucidate the signaling mechanisms involved in IL-1-induced mesangial cell growth.
Main Methods:
- Cultured rat mesangial cells were stimulated with IL-1 and/or group II PLA2.
- Gene expression was analyzed using Northern hybridization.
- [3H]thymidine incorporation was measured to assess DNA synthesis.
- Mesangial cell proliferation was quantified.
- Products of PLA2 activity were identified and tested for biological effects.
Main Results:
- IL-1 stimulated mesangial cells to secrete group II PLA2 and induce its mRNA expression.
- Exogenous group II PLA2 mimicked and amplified IL-1-induced DNA synthesis and cell proliferation.
- Antibodies against group II PLA2 blocked IL-1's stimulatory effect.
- Lysophospholipids, but not fatty acids, produced by group II PLA2 replicated IL-1 and PLA2's mitogenic effects.
Conclusions:
- Group II phospholipase A2 acts as a crucial signaling molecule in IL-1-mediated mesangial cell proliferation.
- The mitogenic effects are mediated through the generation of lysophospholipids.
- Targeting group II PLA2 may offer a therapeutic strategy for glomerulonephritis.